Serum MicroRNA on inflammation: a literature review of mouse model studies.

MicroRNAs (miRNAs) are small non-coding RNA molecules that regulate target gene expression by binding to sequences in messenger RNA processing. Inflammation is a protective reaction from harmful stimuli. MiRNAs can be biomarkers of diseases related to inflammation and are widely expressed in serum. However, overall changes in serum miRNA levels during inflammation have yet to be observed. Here, we selected studies published until 20 January 2020 that examined miRNAs in mouse models of inflammation. Serum microRNA, inflammation, inflammatory and mouse were used as search terms to select articles from PubMed and MEDLINE. Among the articles, sepsis and 18 related miRNAs were mainly examined. Eleven miRNAs were related to brain disease and 10 with fibrosis. Seventeen injury-induced inflammatory disease studies were included, as well as other inflammatory diseases, such as metabolic disease, vascular disease, arthritis, asthma, autoimmune disease, inflammatory bowel disease, and thyroiditis. The data described miRNA-associated downstream pathways associated with inflammation as well as mitochondrial responses, oxidative responses, apoptosis, cell signalling, and cell differentiation. We expect that the data will inform future animal inflammation-related miRNA studies.

Hard X-ray self-seeding commissioning at PAL-XFEL.

A wake monochromator based on a large-area diamond single crystal for hard X-ray self-seeding has been successfully installed and commissioned in the hard X-ray free-electron laser (FEL) at the Pohang Accelerator Laboratory with international collaboration. For this commissioning, the self-seeding was demonstrated with a low bunch charge (40 pC) and the nominal bunch charge (180 pC) of self-amplified spontaneous emission (SASE) operation. The FEL pulse lengths were estimated as 7 fs and 29.5 fs, respectively. In both cases, the average spectral brightness increased by more than three times compared with the SASE mode. The self-seeding experiment was demonstrated for the first time using a crystal with a thickness of 30 µm, and a narrow bandwidth of 0.22 eV (full width at half-maximum) was obtained at 8.3 keV, which confirmed the functionality of a crystal with such a small thickness. In the nominal bunch-charge self-seeding experiment, the histogram of the intensity integrated over a 1 eV bandwidth showed a well defined Gaussian profile, which is evidence of the saturated FEL and a minimal electron-energy jitter (∼1.2 × 10-4) effect. The corresponding low photon-energy jitter (∼2.4 × 10-4) of the SASE FEL pulse, which is two times lower than the Pierce parameter, enabled the seeding power to be maximized by maintaining the spectral overlap between SASE FEL gain and the monochromator.

Distinct function of miR-17-92 cluster in the dorsal and ventral adult hippocampal neurogenesis.

It has been known that the dorsal and ventral areas of the dentate gyrus in the hippocampus have distinct roles in memory and mood behaviors. We previously reported that microRNA miR-17-92 regulates adult hippocampal neurogenesis and mood disorders. Here, we suggest that the miR-17-92 cluster is highly expressed in the ventral than the dorsal dentate gyrus in the adult mouse hippocampus. Deletion of miR-17-92 in the adult hippocampus only affects development of neural progenitors in the ventral dentate gyrus, and miR-17-92 knockout mice have no defects in memory functions. Our results suggest that regional expression of miR-17-92 in the dentate gyrus is associated with their distinct functions in hippocampal neurogenesis and related behaviors.

Hippocampal MicroRNAs Respond to Administration of Antidepressant Fluoxetine in Adult Mice.

Current antidepressant treatments to anxiety and depression remain inadequate, burdened by a significant percentage of misuse and drug side-effects, due to unclear mechanisms of actions of antidepressants. To better understand the regulatory roles of antidepressant fluoxetine-related drug reactions, we here investigate changes of expression levels of hippocampal microRNAs (miRNAs) after administration of fluoxetine in normal adult mice. We find that 64 miRNAs showed significant changes between fluoxetine treatment and control groups by analyzing 626 mouse miRNAs. Many miRNAs in response to fluoxetine are involved in neural-related signaling pathways by analyzing miRNA-target gene pairs using the Kyoto encyclopedia of genes and genomes (KEGG) and Gene Ontology (GO). Moreover, miRNAs with altered expression are mainly associated with the repression of the dopaminergic synapse signals, which may affect hippocampal function after fluoxetine treatment. Our results demonstrate that a number of miRNAs respond to antidepressants even in normal mice and may affect target gene expression, which supports the safety consideration of inappropriate treatment and off-label use of antidepressant drugs.

What intrinsic factors influence responsiveness to acupuncture in pain?: a review of pre-clinical studies that used responder analysis.

BACKGROUND: Not many studies have investigated individual sensitivity to acupuncture. To explore the intrinsic factors related to individual responses to acupuncture, we reviewed published pre-clinical studies using responder analysis on pain. METHODS: We searched the PubMed and EMBASE databases to June 2015. We included pre-clinical reports describing responders and non-responders to anti-nociceptive and analgesic effects of acupuncture in animal study. We identified the potential intrinsic factors which might be related with the response to acupuncture. RESULTS: Totally, 216 potentially relevant articles were retrieved and 14 studies met our inclusion criteria. Rat (n = 1348) and rabbit (n = 56) were used, and only electroacupuncture (EA) was applied as an intervention. Results showed that high levels of cholecystokinin-8 and receptors were associated with poor responsiveness to EA. Endogenous opioids including ß-endorphin and met-enkephalin, descending inhibitory norepinephrine and serotonin system, and hypothalamic 5'-AMP-activated protein kinase seemed to be associated with high-level responses. Spinal levels of neurotransmitters and pro-inflammatory cytokines were also differentially expressed depending on the EA sensitiveness. In the central nervous system, hypothalamus, periaqueductal grey, pituitary gland, and spinal cord were suggested to be involved in the EA responsiveness. Identified individual variations did not seem to be accidental, as the responsiveness to EA was replicated over time. However, methodological issues such as reproducibility, cut-off criteria, and clinical relevance need to be further elaborated. CONCLUSION: Our study suggests that the identification of the biological factors differentiating responders from non-responders is necessary and it may aid in understanding how acupuncture modulates pain.

Gastrodia elata Blume alleviates L-DOPA-induced dyskinesia by normalizing FosB and ERK activation in a 6-OHDA-lesioned Parkinson's disease mouse model.

BACKGROUND: Gastrodia elata Blume (GEB), commonly used medicinal herb, has been reported as a promising candidate for neurodegenerative diseases such as Parkinson's disease. The dopamine precursor, L-3,4-dihydroxyphenylalanine (L-DOPA), is the gold-standard drug for Parkinson's disease, but long-term treatment results in the L-dopa-induced dyskinesia (LID). This study was undertaken to examine the beneficial effects of GEB on L-DOPA induced dyskinesia in 6-hydroxydopamine (6-OHDA)-induced experimental Parkinsonism. METHODS: We tested the effects of GEB on LID in 6-hydroxydopamine hydrochloride-hemiparkinsonian mice. To analyze the dyskinetic anomalies, we measured abnormal involuntary movement (AIM). Immunohistological analyses of pERK and FosB expressions in the striatum are performed to explore the mechanism of GEB on LID. RESULTS: The finding of this study demonstrated that GEB (200, 400 and 800 mg/kg) alleviated L-dopa induced AIMs in a dose-dependent manner. In each integrative AIM subtype analysis, we also found that the GEB (400 and 800 mg/kg) treatment decreased L-DOPA-induced axial, limb, orolingual, and locomotive AIMs compared to the LID group. In addition, GEB normalized the abnormal LID-induced increase of pERK1/2 and FosB, the immediate early genes of LID in the striatum. CONCLUSIONS: In conclusion, our results provide a novel insight into the pharmacological actions of GEB that could have a benefit for PD patients through the reduction of LID.

Detection of earthquake-induced damage in a framed structure using a finite element model updating procedure.

Damage of a 5-story framed structure was identified from two types of measured data, which are frequency response functions (FRF) and natural frequencies, using a finite element (FE) model updating procedure. In this study, a procedure to determine the appropriate weightings for different groups of observations was proposed. In addition, a modified frame element which included rotational springs was used to construct the FE model for updating to represent concentrated damage at the member ends (a formulation for plastic hinges in framed structures subjected to strong earthquakes). The results of the model updating and subsequent damage detection when the rotational springs (RS model) were used were compared with those obtained using the conventional frame elements (FS model). Comparisons indicated that the RS model gave more accurate results than the FS model. That is, the errors in the natural frequencies of the updated models were smaller, and the identified damage showed clearer distinctions between damaged and undamaged members and was more consistent with observed damage.

Integrative analysis of plasma and substantia nigra in Parkinson's disease: unraveling biomarkers and insights from the lncRNA-miRNA-mRNA ceRNA network.

Introduction: Parkinson's disease (PD) is a rapidly growing neurological disorder characterized by diverse movement symptoms. However, the underlying causes have not been clearly identified, and accurate diagnosis is challenging. This study aimed to identify potential biomarkers suitable for PD diagnosis and present an integrative perspective on the disease. Methods: We screened the GSE7621, GSE8397-GPL96, GSE8397-GPL97, GSE20163, and GSE20164 datasets in the NCBI GEO database to identify differentially expressed (DE) mRNAs in the substantia nigra (SN). We also screened the GSE160299 dataset from the NCBI GEO database to identify DE lncRNAs and miRNAs in plasma. We then constructed 2 lncRNA-miRNA-mRNA competing endogenous RNA (ceRNA) regulatory networks based on the ceRNA hypothesis. To understand the biological function, we performed Kyoto Encyclopedia of Genes and Genomes pathway and Gene Ontology analyses for each ceRNA network. The receiver operating characteristic analyses (ROC) was used to assess ceRNA results. Results: We identified 7 upregulated and 29 downregulated mRNAs as common DE mRNAs in the 5 SN datasets. In the blood dataset, we identified 31 DE miRNAs (9 upregulated and 22 downregulated) and 332 DE lncRNAs (69 upregulated and 263 downregulated). Based on the determined interactions, 5 genes (P2RX7, HSPA1, SLCO4A1, RAD52, and SIRT4) appeared to be upregulated as a result of 10 lncRNAs sponging 4 miRNAs (miR-411, miR-1193, miR-301b, and miR-514a-2/3). Competing with 9 genes (ANK1, CBLN1, RGS4, SLC6A3, SYNGR3, VSNL1, DDC, KCNJ6, and SV2C) for miR-671, a total of 26 lncRNAs seemed to function as ceRNAs, influencing genes to be downregulated. Discussion: In this study, we successfully constructed 2 novel ceRNA regulatory networks in patients with PD, including 36 lncRNAs, 5 miRNAs, and 14 mRNAs. Our results suggest that these plasma lncRNAs are involved in the pathogenesis of PD by sponging miRNAs and regulating gene expression in the SN of the brain. We propose that the upregulated and downregulated lncRNA-mediated ceRNA networks represent mechanisms of neuroinflammation and dopamine neurotransmission, respectively. Our ceRNA network, which was associated with PD, suggests the potential use of DE miRNAs and lncRNAs as body fluid diagnostic biomarkers. These findings provide an integrated view of the mechanisms underlying gene regulation and interactions in PD.

Peripheral Rho-associated protein kinase activation mediates acupuncture analgesia.

Background: Acupuncture has been proven effective for various types of pain, and peripheral molecular signals around acupuncture-treated areas have been suggested to contribute to the analgesic effects of acupuncture. However, the underlying mechanism from these peripheral molecular signals to central ones remains unclear. The purpose of this study was to investigate whether peripheral Rho-associated protein kinase (ROCK) activation induced by acupuncture treatment mediates acupuncture analgesia, and also to investigate the relationship between ROCK activation and extracellular signal-regulated kinase (ERK), which has previously been proven to mediate acupuncture analgesia and other related molecular changes during acupuncture. Methods: Acupuncture was treated at the bilateral GB34 acupoints of C57BL/6 mice, after which changes in ROCK activation and the location of its expression in the skin were analyzed. To verify the role of ROCK in acupuncture analgesia, we administrated ROCK inhibitor Y-27632 (0.3 µg/ul) into the skin before acupuncture treatment with formalin and complete Freund adjuvant (CFA) induced pain models, then the nociceptive responses were analyzed. Results: Acupuncture treatment produced ROCK2 activation in the skin after 30 and 60 min, and the histological analyses revealed that ROCK2 was activated in the fibroblast of the dermis. The acupuncture-induced ROCK2 expression was significantly attenuated by the ERK inhibitor, whereas phospho-ERK expression was not inhibited by ROCK inhibitor. In both the formalin- and CFA-induced mouse pain models, acupuncture analgesia was blocked by ROCK inhibitor administration. Conclusion: Acupuncture treatment-induced ROCK2 expression is a downstream effector of phospho-ERK in the skin and plays a crucial role in acupuncture analgesia.

Peripheral mast cells derive the effects of acupuncture in Parkinson's disease.

This research investigates the peripheral mechanisms of acupuncture in treating Parkinson's disease (PD), a progressive neurodegenerative disorder marked by motor impairments. While the central mechanisms of acupuncture have been extensively studied, our focus lies in the peripheral mechanisms at the acupoints, the sites of acupuncture signal initiation. Employing a PD model, we analyzed the local responses to acupuncture stimulation at these points. Our key finding was a significant elevation in both the number and activity of mast cells (MCs) in the peripheral tissues following acupuncture. Intriguingly, pre-treatment with an MC stabilizer diminished the acupuncture's therapeutic effects on PD symptoms. Similarly, local anesthesia with lidocaine at the acupoints attenuated the symptom improvement typically observed with acupuncture. Meanwhile, the augmentation of MC activity induced by acupuncture was significantly impeded by cromolyn, an MC stabilizer, but remained unaffected by lidocaine. This finding suggests that MC activity is a more upstream regulator of acupuncture effects compared to nerve conduction. This study provides groundbreaking insights into the initiation and transmission of acupuncture signals, highlighting the significant role of peripheral MC modulation in PD treatment.

DHPLC is a highly sensitive and rapid screening method to detect BRAF(V600E) mutation in papillary thyroid carcinoma.

The BRAF(V600E) mutation has been reported to occur in 30% to 80% of papillary thyroid carcinomas (PTCs). Although direct sequencing is the method most commonly used to identify mutations, this technique is not sensitive enough to accurately detect low level mutation. To determine the optimal diagnostic method for detecting the BRAF(V600E) mutation in PTC, we compared the diagnostic efficacy of four representative detection methods in formalin-fixed paraffin-embedded thyroid tissues obtained from 40 patients diagnosed with PTC. To detect the BRAF(V600E) mutation, we amplified exon 15 of the BRAF gene and performed mutational analysis with direct sequencing, denaturing high-performance liquid chromatography (DHPLC), pyrosequencing and colorimetric assay. The BRAF mutation was detected in 33 cases (82.5%) by DHPLC, 23 cases (57.5%) by direct sequencing, 22 cases (55.0%) by pyrosequencing, and 37 cases (92.5%) by colorimetric assay. The sensitivity, negative predictive value and accuracy of DHPLC were 100%. The specificity and positive predictive values for DHPLC, direct sequencing and pyrosequencing were 100%, and for colorimetric assay they were 14.3% and 83.8%, respectively. The kappa value for DHPLC was a perfect 1.0, which was superior to the other methods. In conclusion, DHPLC is a sensitive, specific and accurate method for detecting the BRAF(V600E) mutation, especially low level mutation, in PTC.

The effect of acupuncture on pain and swelling of arthritis animal models: A systematic review and meta-analysis.

Arthritis, the inflammation of joints, attributes to the patient's pain, joint deformation, and limited range of motion. Emerging studies have shown the effects of acupuncture on different types of arthritis. We aimed to assess the effects of acupuncture on arthritis animal models and summarize the related mechanisms. We retrieved studies that met our criteria from PubMed, MEDLINE, EMBASE and the Research Information Service System. The quality assessment was evaluated by using the Systematic Review Centre for Laboratory Animal Experimentation's risk of bias tool. The pain withdrawal latency, pain withdrawal threshold, and paw volume data were digitized using Engauge Digitizer software. The meta-analysis was performed, and the figures were generated using RevMan software. The meta-analysis of data from 21 animal studies revealed that acupuncture increased tolerance to pain stimuli, and reduced swelling in arthritis animals. Although the number of included studies is insufficient, the results suggest acupuncture to be effective in improving arthritis-induced inflammation and pain by regulating the nervous and immune system.

The effects of acupuncture on sleep disorders and its underlying mechanism: a literature review of rodent studies.

Sleep is a set of physiological processes mainly under neurobiological regulation that affect several physiological systems, and sleep disorders are a condition where normal sleep patterns are disturbed. Clinical studies have confirmed the effects of acupuncture on sleep duration and quality. Although many studies have explored the therapeutic effects of acupuncture on sleep disorders, the mechanisms are unclear. We investigated the mechanism of acupuncture efficacy in a rodent model of sleep disorders and evaluated the therapeutic effects of acupuncture treatment. According to our results, sleep disorders are associated with several brain regions and neurotransmitters. Furthermore, this review showed that neurological processes, such as catecholamine and BDNF signaling pathways, can be regulated by acupuncture, which is a crucial aspect of the acupuncture mechanism in sleep disorders.

Effect of acupuncture on pain and substance P levels in middle-aged women with chronic neck pain.

Chronic neck pain is a leading health issue affecting a significant proportion of the global population. Multiple treatment options for chronic neck pain include anti-inflammatory drugs and analgesics. Acupuncture has been widely used for the treatment of chronic pain. In this study, we aimed to determine the efficacy of acupuncture for female patients with chronic neck pain. Twenty-three participants were enrolled in the study, and participants waited 4 weeks without acupuncture treatment and then received 4 weeks of treatment. One-way ANOVA with repeated measures was used to determine differences in the visual analogue scale (VAS), neck disability index (NDI), and substance P (SP) over time. The subjects' pain intensity and degree of disability due to neck pain were measured as primary outcomes. SP in the blood was also analyzed as a secondary outcome. There was no significant difference between the VAS score and NDI value of baseline and after 4 weeks waiting. However, there was an improvement in both VAS and NDI after 4 weeks treatment. SP level was decreased after 4 weeks treatment. We could conclude that acupuncture is effective in alleviating chronic neck pain. Moreover, our findings revealed the efficacy of acupuncture on chronic pain with potential underlying biological mechanisms.

Effects of acupuncture on gastrointestinal diseases and its underlying mechanism: a literature review of animal studies.

Acupuncture is a non-pharmacological traditional Chinese medical technique that has been used for various types of gastrointestinal (GI) diseases in Eastern medicine. However, the specific mechanisms underlying acupuncture treatment in the GI tract have not yet been elucidated. In this study, we searched the electronic databases PUBMED, EMBASE, and MEDLINE and identified 30 eligible studies that were summarized in this review. This review demonstrates that treatments, including both manual and electroacupuncture, have therapeutic mechanisms in diverse GI diseases. The underlying mechanisms are broadly divided into the following: changes in gene expression in the gastric mucosa or nuclei of the solitary tract, metabolic change induction, regulation of anti-inflammatory substances, vagal activity increase, change in functional connectivity between brain regions, and control of the number of neurons related to GI diseases. Although this study is limited in that it does not represent all types of GI diseases with different acupuncture methods, this study identified acupuncture as effective for GI diseases through various biological mechanisms. We hope that our study will reveal various mechanisms of acupuncture in GI diseases and play an important role in the therapy and treatment of GI diseases, thus advancing the field of study.

Autonomous vehicles and street design: Exploring the role of medians in enhancing pedestrian street crossing safety using a virtual reality experiment.

As traffic lanes and on-street parking spots can potentially be downsized with the introduction of autonomous vehicles (AVs), the possibility of additional spare road space becoming available arises in future urban streets. While discussions on converting the leftover space into pedestrian-friendly alternatives exist, allocating that limited space to which alternative is foreseen to be another practical issue shared in both urban and transportation planning. However, evidence-based guidance on the issue provided from the actual verification on whether or to what extent the proposed alternatives may have an effect seems to be absent. Therefore, with an emphasis on pedestrian safety, this study focused on the "median strip" alternative as a first example and, through a VR simulation experiment aimed at empirically examining its suggested role on enhancing street crossing safety and further exploring its possible influence on pedestrians' trust toward autonomous driving. With 99 participants, perceived safety (individual assessments of safety), performance-based safety (crossing success/abandonment and collision occurrence), and trust were either questioned or recorded for nine scenarios with varying crossing conditions. A combination of multilevel models and cross-tabulation results indicate that medians seem especially significant in ensuring the performance-based safety results of pedestrians even when AVs are driving at high speeds or with smaller gaps, thus suggesting it a win-win option for both. Insights and implications on the role and management of medians in future streets are further provided.

The Effect of Acupuncture on Modulating Inflammatory Cytokines in Rodent Animal Models of Respiratory Disease: A Systematic Review and Meta-Analysis.

Purpose: Although respiratory diseases (RD) are rapidly becoming a global health issue due to their high mortality and prevalence, there are limitations to the currently available treatments. Acupuncture has been recognized to mitigate many diseases by reducing inflammation and modulating cytokines. However, no systematic analysis has been performed to examine the effects of acupuncture on RD. We aimed to evaluate the effects of acupuncture on rodent animal models of RD. Methods: PubMed, EMBASE, MEDLINE, and the Research Information Service System were searched to retrieve studies that met our inclusion/exclusion criteria. The quality of each included study was evaluated using a 10-item checklist modified from the Collaborative Approach to Meta-Analysis and Review of Animal Data from Experimental Studies. With adequate data extracted, meta-analysis was performed using RevMan software. Results: A total of 18 studies were included, and the mean quality assessment was 5.7. The meta-analysis revealed that acupuncture had a significant effect on changing the cytokine levels, including pro-/anti-inflammatory, Th1-, Th2- and Th17- specific cytokines. Conclusion: Although there were limitations in the number of included studies, the results suggest that acupuncture can be a possible treatment for RD through its modulation of various cytokines, leading to reduced inflammation.

The Extracellular MicroRNAs on Inflammation: A Literature Review of Rodent Studies.

Inflammation is an indispensable biological process stimulated by infection and injuries. Inflammatory mechanisms related to extracellular vesicles (EVs), which are small membrane structures carrying various molecules, were summarized in this review. Emerging evidence from animal studies has highlighted the role of EVs in modulating inflammatory responses, by transporting various molecules involved in host defense. In this review, we have discussed the role of EV miRNAs in inflammation. Rodent studies associated with extracellular miRNAs in inflammatory diseases, published from 2012 to 2022, were explored from PUBMED, EMBASE, and MEDLINE. A total of 95 studies were reviewed. In summary, EV-associated miRNAs play a key role in various diseases, including organ injury, immune dysfunction, neurological disease, metabolic syndrome, vesicular disease, arthritis, cancer, and other inflammatory diseases. Diverse EV-associated miRNAs regulate inflammasome activation and pro- and anti-inflammatory cytokine levels by targeting genes.

Changes of local microenvironment and systemic immunity after acupuncture stimulation during inflammation: A literature review of animal studies.

An increasing number of studies have demonstrated the underlying mechanisms by which acupuncture therapy mediates both local and systemic immunomodulation. However, the connection between alterations in the local microenvironment and the resulting change in systemic immunity remains unclear. In this review, we focus on cell-specific changes in local immune responses following acupuncture stimulation and their link to systemic immune modulation. We have gathered the most recent evidence for chemo- and mechano-reactive changes in endothelial cells, neutrophils, macrophages, and mast cells in response to acupuncture. Local signaling is then related to the activation of systemic neuro-immunity including the cholinergic, adrenal, and splenic nervous systems and pain-related neuromodulation. This review aims to serve as a reference for further research in this field.

Co-Treatment with the Herbal Medicine SIP3 and Donepezil Improves Memory and Depression in the Mouse Model of Alzheimer's Disease.

BACKGROUND: Alzheimer's disease (AD) is a lethal, progressive neurodegenerative disorder that has been linked to a deficiency of the neurotransmitter acetylcholine. Currently, many acetylcholinesterase inhibitors, such as donepezil, are widely used for the treatment of AD. On the other hand, the efficacy of long-term donepezil use is limited. SIP3, a mixture of three herbal extracts from Santalum album, Illicium verum, and Polygala tenuifolia, is a new formula derived from traditional Korean herbal medicine. OBJECTIVE: We assessed the synergistic effect of SIP3 and donepezil co-treatment on symptoms of AD using APP/PS1 transgenic mice. METHODS: In this study, a Drosophila AD model and SH-SY5Y clles were used to assess the toxicity of SIP3, and APPswe/PS1dE9 (APP/PS1) transgenic mice were used to evaluate the cognitive-behavioral and depression-like behavior effect of SIP3 and donepezil co-treatment on symptoms of AD. The cerebral cortex or hippocampus transcriptomes were analyzed by RNA sequencing and miRNA to investigate the molecular and cellular mechanisms underlying the positive effects of SIP3 on AD. RESULTS: In the passive avoidance test (PAT) and Morris water maze (MWM) test, the combination of SIP3 and donepezil improved the learning capabilities and memory of APP/PS1 mice in the mid-stage of AD compared to the group treated with donepezil only. In addition, co-administration of SIP3 and donepezil effectively reduced the depression-like behavior in the forced swimming and tail suspension tests. Furthermore, RNA sequencing of the cerebral cortex transcriptome and miRNA of the hippocampus showed that the gene expression profiles after a low dose SIP3 co-treatment were more similar to those of the normal phenotype mice than those obtained after the donepezil treatment alone. The Gene Ontology (GO) and the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways, showed that differentially expressed genes were involved in the locomotor behavior and neuroactive ligand-receptor interactions. These results suggest that a co-treatment of low dose SIP3 and donepezil improves impaired learning, memory, and depression in the mid-stage of AD in mice. CONCLUSION: Co-treatment of low dose SIP3 and donepezil improves impaired learning, memory, and depression in the mid-stage of AD in mice.